Preparation of carotenoid compounds



United States Patent PREPARATION OF CAROTENOID COMPOUNDS Joseph DonaldSurmatis, West Caldwell, N.J., assignor to Hoifmann-La Roche Inc.,Nutley, N.J., a corporation of New Jersey No Drawing. Originalapplication Oct. 24, 19:8, Ser. No. 769,323, now Patent No. 2,945,888,dated July 19, 1960. Divided and this application Dec. 1, 1959, Ser. No.856,491

5 Claims. (Cl. 260-666) This invention relates to novel chemicalprocesses and to novel chemical compounds useful as intermediatestherein. More particularly, the invention relates to novel processes ofsynthesizing carotenoid compounds, and to novel di(phosphonium halide)compounds and novel diphosphine compounds by means of which saidprocesses can be effected.

This application is a division of my copending appllcation Serial No.769,323, filed October 24, 1958 now US. Patent 2,945,888, issued July19, 1960.

A general and comprehensive survey of the invention is afforded by thefollowing flow sheet:

In the preceding flow sheet,

The symbol Z represents a divalent radical selected from the groupconsisting of the radical --CH=CH- and the radical -CEC;

The symbol X represents a halogen, e.g. chlorine or bromine;

The symbol R represents a monovalent aryl radical, e.g. phenyl,naphthyl, p-methoxyphenyl; preferably a monovalent mononuclear arylhydrocarbon radical, e.g. phenyl or tolyl;

The symbol Q represents a monovalent radical containing a plurality ofolefinic bonds; preferably, a mono valent higher hydrocarbon radicalcontaining a plurality of olefinic bonds; still more preferably, amonovalent higher aliphatic or cycloaliphatic-aliphatic hydrocarbonradical containing a plurality of olefinic bonds, at least some of whichare in conjugation.

It will be seen from the flow sheet that the comprehensive generalprocess referred to above comprises convetting the C diol represented bygeneral Formula I to the corresponding C dihalide represented by generalFormula 11, e.g. by reaction with a concentrated aqueous hydrohalicacid; reacting the C dihalide with a triarylphosphine of the generalformula R P (wherein the symbol R has the meaning indicated above),thereby forming a novel di(phosphonium halide) compound represented bygeneral Formula III; dehydrohalogenating the latter, e.g. by treating itwith phenyl lithium, methyl lithium, Grignard reagents, or similarorgano metal compounds, thereby forming a novel diphosphine compoundrepresented by the general Formula IV; and reacting the latter withapproximately two molar proportions of a polyene aldehyde represented bythe general Formula V, thereby forming an intermediate compound (notshown by formula in the flow sheet) which spontaneously decomposes toyield the carotenoid compound represented by the general Formula VI. Inthe event that the radical Z in the carotenoid Compound VI is theradical -CEC, said carotenoid Compound VI can optionally be subjected toa process of selective hydrogenation, according to methods known per se(e.g. partial hydrogenation with elemental hydrogen in the presence of aselective hydrogenation catalyst, such as palladium-lead) therebyconverting the radical -CEC to the radical -CH=CH.

It will be apparent that a characteristic novel step in processesaccording to the invention is that improved step which comprisescondensing a diphosphine compound represented by the general Formula IVabove with a polyene aldehyde represented by the general Formula Vabove. A preferred embodiment of this novel step comprises condensing adiphosphine compound selected from the group consisting of2,7-dimethyl-2,6-octadien-4-ynel,8-di(-ylidene triphenylphosphine) and2,7-dimethyl- 2,4,6-octatriene-1,8,di(-ylidene triphenylphosphine) withapproximately two molar proportions of a polyene aldehyde represented bythe general formula wherein the symbol n represents a small integer,preferably 1 or 2.

It will thus be seen that one preferred specific embodiment of theinvention resides in a process which comprises condensing2,7-dimethyl-2,6-octadien-4-yne-1,8-di- (-ylidene triphenylphosphine)with approximately two molar proportions of5-(2,6,6-trimethyl-l-cyclohexen-1- yl)-3-methyl-2,4-pentadien-1-a1,thereby forming dehydro-B-carotene.

Another preferred specific embodiment of the invention resides in aprocess which comprises condensing 2,7- dimethyl 2,4,6octatriene-l,8-di(-ylidene triphenylphosphine) with approximately twomolar proportions of 5-(2,6,6 trimethyl 1 cyclohexen-l-yl) 3 methyl-2,4-pentadien-l-al, thereby forming ,B-carotene.

Still another preferred specific embodiment of the invention relates toa process which comprises condensing 2,7-dimethyl 2,4,6octatriene-1,8-di(-ylidene triphenylphosphine) with approximately twomolar proportions of9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-3,7-dimethyl-2,4,6,8-nonatetraen-1-al, thereby forming decapreno-fi-carotene.

Similarly, by condensing 2,7-dimethyl 2,4,6 octatriene-1,8-di(-y1idenetriphenylphosphine) with approximately two molar proportions of3,7,ll-trimethyl-2,4, 6,10-dodecatetraen-1-al, the carotenoid compoundlycopene is produced. Likewise, by condensing 2,7-dimethyl-2,4,6-octatriene-l,8-di(-ylidene triphenylphosphine) with approximatelytwo molar proportions of 3,7,11-trimethyl- 2,6,l0-dodecatrien-l-al(farnesal), the carotenoid compound tetrahydrolycopene is produced,having the formula:

(VIII) Another characteristic novel step taught by the present inventionis the preparation of the novel di(triarylphosphonium halides) ofgeneral Formula III shown in the above flow sheet. A preferred method ofeflecting the preparation of these compounds comprises treating thecorresponding halides, general Formula II in the flow sheet, especiallythe chlorides or bromides, with triphenylphosphine ortri(p-tolyl)phosphine in the presence of a condensation catalyst, suchas iodine. Preferred products produced by this aspect of the inventionare those in which all aryl radicals present are monovalent mononucleararyl hydrocarbon radicals, such as phenyl or tolyl, particularly phenyl.It follows that certain preferred embodiments of the noveldi(triarylphosphonium halide) products of the invention are thoserepresented by the general formula wherein the symbol Z represents adivalent radical selected from the group consisting of -CH=CH-- and -CC-, the symbol X represents a halogen selected from the group consistingof chlorine and bromine, and thesymbol R represents a radical selectedfrom the group consisting of phenyl and tolyl.

The invention is further disclosed in the following examples, which areillustrative but not limitative thereof. Temperatures are stated indegrees centigrade, uncorrected.

Example 1 166 g. (1.0 mol) of 2,7-dimethyl-1,7-octadien-4-yne- 3,6-diol(Deemer et al., J. Am. Chem. Soc., 70, 154 [1948]) was suspended in 150ml. of ethyl alcohol and was cooled to minus 10. Then 1200 ml. ofconcentrated (48%) hydrobromic acid was placedin a dropping funnel andadded in 30 minutes While stirring. The temperature of the reactionmixture was kept at to minus during the addition. Stirring was continuedfor an additional minutes. The light tan colored crystalline dibromidewhich formed was filtered by suction in a nitrogen atmosphere and washedon the filter, first with dilute sodium bicarbonate solution and thenwith water. The solid was dried in vacuum at 40. The product obtained,2,7-dimethyl-Z,6-octadien-4-yn-1,8-ylene-dibromide (which can also beidentified, alternatively, by the nomenclature 1,8-dibromo-2,7-dimethyl2,6 octadien-4- yne), was used for the next step without furtherpurification.

A solution of 838 g. (3.2 mols) of triphenylphosphine in 3 liters ofbenzene was heated to 40. While stirring and maintaining the temperatureat 40-45, a solution of 458 g. (1.57 mols) if2,7-dimethyl-2,61octadien-4-yn- 1,8-ylene dibromide, dissolved in 500ml. of benzene, to which solution had been added 0.2 g. of iodine, wasdropped into the warm triphenylphosphine solution over aperiod of twohours. Some crystalline solid began to form soon after the addition wasstarted. After all the dibromide had been added, stirring of thereaction mixture was continued for an additional period of about fourhours, and then the reaction mixture was allowed to stand overnight. Thewhite crystalline precipitate was then filtered ofi, washed with warmbenzene and with petroleum ether, in turn, and dried under vacuum. Therewas thus obtained 2,7-dimethy1-2,6-octadien-4-yn- 1,8 ylenedi(triphenylphosphonium bromide), having M.P. of 223-227. For analysis,a small portion of the material was recrystallized from methanol-ethylacetate. The material then melted at 238.

Analysis.Caled for C H Br P: C, 67.65%; H, 5.18%. Found: C, 67.58%; H,5.31%.

To 21.9 g. (0.26 mol) of phenyl lithium in 500 ml. of ether was added g.(0.12 mol) of the solid, powdered2,7-dimethyl-2,6-octadien-4-yn-1,8-ylene-di(triphenylphosphoniumbromide) over a period of about 30 minutes. The ether refluxed duringaddition and the color of the reaction mixture turned to a dark brown,resulting in the formation of 2,7-dimethyl-2,6-octadien-4-yne-l,8-di(-ylidene triphenylphosphine) After all of the phenyl lithium had beenthus reacted, there was added to the reaction mixture, dropwise, over aperiod of about-an hour, a solution of 48' g. (0.22- mol) of5-(2,6,6-trimethyl-l-cyclohexene1-yl)-3-methyl-2,4-pentadien-l-al (Kuhnet al.,* U.S.P. 2,239,491), dissolved in 100 m1. of ether. The reactionmixture refluxed vigor-. ously during theaddition of the aldehyde andthe color. turned to a' dark red. The mixture was stirred at refluxtemperature for four hours in a nitrogen atmosphere. The contents of theflask were cooled to 0 and 200 ml. of methanol was added. The reactionmixture was concentrated to approximately one-third its volume bydistilling otf solvent under vacuum. The residual mixture was stirredfor three hours at minus 10". The crystalline: precipitate was filteredoff by suction and washed on the filter with a little methanol and'wasthen recrystallized from ethyl acetate. An additional quantity ofproduct was obtained by concentrating all the mother liquors to a syrup,washing several times with methanol, dissolving the remaining residue inethyl acetate, and cooling the ethyl acetate solution overnight at minus10, thus precipitating a second crop of product which was filtered 01fTo a solution of 83 g. (0.5 mol) of 2,7-dimethyl-1,7-octadien-4-yne-3,6-diol in 500 ml. of toluene were added 5 ml. ofquinoline and 10 g. of palladium-lead on calcium carbonate catalyst[Lindlar, Helvetica Chimica Acta, 35, 450 (1952)]. Hydrogen gas waspassed into the flask at a pressure of 2-3 p.s.i. gauge. When thetheoretical quantity of hydrogen had been taken up, the hydrogenationwas interrupted and the reaction mixture was filtered. The separatedcatalyst was slurried twice, each time with 100 ml. of warmacetone, andthe acetone was added to the toluene filtrate. The mixture thus obtainedwas distilled to dryness under vacuum. The crystalline residue wasdissolved in warm petroleum ether, and the solution was chilled. Therewas thus obtained 2,7-dimethyl-l,4,7- octatriene-3,6-diol, M.P. 69-70".

A solution of 36.6 g. (0.2 mol) of 2,7-dimethyl-1,4,7-

octatriene-3,6-diol in 100 ml. of ethanol was cooled to minus 10". Then250 ml. of concentrated (48%) hydrobromic acid was added dropwise. Afterall the hydrobromic acid had been added, the reaction mixture wasstirred at 0 to minus 10 for an additional period of approximately 15minutes. The crystalline product was filtered off by suction in anitrogen atmosphere. The solid material so recovered was washed with 5%sodium bicarbonate solution and dried under vacuum at 35. There was thusobtained 2,7-dimethyl-2,4,6-octatrien-1,8- ylene dibromide (alternativenomenclature: 1,8-dibromo- 2,7-dimethyl-2,4,6-octatriene), M.P. '70-7l.

To a solution of 131g. (0.5 mol) of triphenylphosphinein 400 ml. ofbenzene was added dropwise over a period of four hours, while stirring,and at 40-45, a solution of 53 g. (0.18 mol) of2,7-dimethy1-2,4,6-octatrien-1,8-ylene dibromide in 400 m1. of benzeneto which 0.1 g. of iodine had previously been added. Crystals began toform as soon as the addition of the dibromide was started. The reactionmixture was stirred at 4045 for four hours and then was allowed to standovernight. The next day the precipitated material was filtered oif,washed on the filter with benzene and then with petroleum ether, anddried under vacuum at 50. There was thus obtained2,7-dimethyl-2,4,6-octatrien-1,8-ylene di(triphenylphosphonium bromide).An analytical sample, recrystallized from methanol-ethyl acetate, meltedat 250.

Analysis.Ca1d for C H Br P: C, 67.20%; 5.56%. Found: C, 67.49%; H,5.42%.

To 9.25 g. (0.11 mol) of phenyl lithium in 150 ml. of ether was added 46g. (0.056 mol) of solid 2,7-dimethyl- 2,4,6-octatrien-1,8-ylenedi(triphenylphosphonium bromide) as a powder, over a period of 30minutes. The reaction mixture turned a deep purple-red while the termperature rose to about 30. The reaction mixture was stirred for one hourto complete the dehydrobromination, thereby forming2,7-dimethyl-2,4,6-octatrien-1,8-ylene di-(-ylidene-triphenylphosphine).

To the thus obtained reaction mixture containing 2,7-dimethyl-2,4,6-octatrien-1,8-ylene di(-ylidene triphenylphosphine) wasadded dropwise, over a period of one hour, a solution of 24 g. (0.11mol) of5-(2,6,6-trimethy1-l-cyclohexen-1-yl)-3-methyl-2,4-pentadien-l-al (Kuhnet al., US. Patent 2,239,491) in 50 ml. of ether. During addition of thealdehyde, the reaction mixture began to reflux and turn to a deep redcolor. After all the aldehyde had been added, the warm reaction mixturewas stirred for four hours in a nitrogen atmosphere. The reactionmixture was then cooled to minus 20 and 200 ml. of methanol was added.The thus obtained mixture was cooled to minus 20 for four hours, andthen a violet colored precipitate was filtered 01f, washed with water,ethanol and finally with petroleum ether, and dried in vacuum. There wasthus obtained all-trans-fi-carotene, M.P. 174-176", which in a mixedmelting point determination with an authentic sample ofall-trans-fi-carotene showed no lowering of the melting point. Afterrecrystallization from benzene-methanol, the all-trans-fi-caroteneproduct had a melting point of 182.

Example 3 To a solution of 8.4 g. (0.1 mol) of phenyl lithium in 150 ml.of ether was added over a period of about 30 minutes, while stirring,42.6 g. (0.052 mol) of solid 2,7-

dimethyl-2,4,6-octatrien-1,8-ylene. di(triphenylphosphonium bromide) inpowdered form. The reaction mixture was stirred for a further period ofone hour to complete the dehydrobromination, resulting in the formationof 2,7- dimethyl 2,4,6 octatriene 1,8 di(-ylidene triphenylphosphine).

To the reaction mixture thus obtained, was added, over a period of onehour, while stirring, a solution of 28.4 g. (0.1 mol) of9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-3,7-dimethyl-2,4,6,8-nonatetraen-1-al (vitamin A aldehyde) in 100 ml. ofether; resulting in refluxing of the reaction mixture. After completionof addition of aldehyde, stirring was continued at reflux temperature,for an additional period of four hours. The reaction mixture was thencooled to minus 20 and 200 ml. of methanol was added. The resultingmixture was stirred at minus 20 overnight. Then the mixture wasfiltered, and the product on the filter was Washed with a littlemethanol and then with a little petroleum ether. The washed, dark violetcrystals were dried under vacuum. The crude material thus obtained wasrecrystallized from methylene chloride-methanol, resulting inall-trans-decapreno-ficarotene, i.e.1,26-di(2,6,6-trimethyl-l-cyclohexen-l-yl)- 3,7,11,16,20,24 hexamethyl1,3,5,7,9,11,13,15,17,19,2l, 23,25-hexacosatridecaene; M.P. 191.

Example 4 To a solution of 16.8 g. (0.2 mol) of phenyl lithium in 300m1. of ether was added, over a period oi 30 minutes,

while stirring, 82 g. (0.10 mol) of solid 2,7-dimethyl-2,6-octadien-4-yn-1,8-ylene di(triphenylphosphonium bromide) as a finepowder. The reaction m xture was stirred for one hour, then a solutionof 56.8 g. (0.2 mol) of 9- (2,6,6 trimethyl-1-cyclohexen-1-yl)3,7-dimethyl-2,4,6,8- nonatetraen-l-al (vitamin A aldehyde) in 200 ml.of ether was added over a period of one hour. Stirring was thencontinued at reflux temperature for four hours. The reaction mixture wasthen cooled with an ice bath and 400 ml. of methyl alcohol was added allat once. The reaction mixture was stirred about 30 minutes, then wasconcentrated to about one-half its original volume by distillation undervacuum. The remaining solution was cooled at minus 20 for four hours andfiltered. The dehydrodecapreno-B-carotene, i.e.l,26-di(2,6,6-trimethyl-1-cyclohexen-l-yl) 3,7,l1,l6,20,24hexamethyl-l,3,5,7,9,ll,- 15,l7,19,21,23,ZS-hexacosadodecaen-l3-yne,which was obtained as a dark red crystalline product, was purified byrecrystallization from methylene chloride-methanol. It melted at 189 andhad U.V. max. at 481 and S13-5l4 m in petroleum ether.

I claim:

1. In the preparation of carotenoid compounds, the improvement whichcomprises condensing a polyene aldehyde with a diphosphine compoundrepresented by the general formula wherein the symbol Z represents adivalent radical selected from the group consisting of --CH=OH- and-CEC, and the symbol R represents a monovalent aryl radical.

2. A process of making a carotenoid compound which comprises condensinga diphosphine compound represented by the general formula wherein Zrepresents a divalent radical selected from the group consisting ofCH=CH- and CEC, and R represents a monovalent mononuclear anylhydrocarbon radical,

with approximately two molar proportions of a polyene aldehyderepresented by the general formula wherein the symbol n represents asmall integer.

3. A process of making dehydro-B-carotene which comprises condensing2,7-dimethy1-2,6-octadien-4-yne-1,8-di- (-ylidene triphenylphosphine)with approximately two molar proportions of5-(2,6,6-trimethyl-l-cyclohexen-lyl -3 -methyl-2,4-pentadien-1 -a1.

4. A process of making B-carotene which comprises condensing2,7-dimethyl 2,4,6 octatriene1,8-di(-ylidene triphenylphosphine) withapproximately two molar proportions of 5-(2,6,6-trimethyl 1cyclohexen-1-yD-3- UNITED STATES PATENTS References Cited in the file ofthis patent 2,239,491 et a1 Apr. 22, 1941 2,917,539 Isler et a1. Dec.15, 1959

4. A PROCESS OF MAKING B-CAROTENE WHICH COMPRISES CONDENSING2,7-DIMETHYL-2,4,6-OCTATRIENE-1,8-DI(-YLIDENE TRIPHENYLPHOSPHINE) WITHAPPROXIMATELY TWO MOLAR PROPORTIONS OF5-(2,6,6-TRIMETHYL-1-CYCLOHEXEN-1-YL)-3METHYL-2,4-PENTADIENE-1-AL.